The phenomenon of multiple drug resistance is known, and is not restricted only to anticancer agents. Various explanations have been given to this day, to help understanding the mechanisms involved. Concerning the behavior of the cancer tumor cells, it has been possible to identify several different resistance systems: for example, in relation with the cell membrane permeability, the involvement of a specific glycoprotein (P-gp) has been recognized, but it is accepted that other proteinic factors can be involved.
This phenomenon needs to be addressed in its varied, if not complicated aspects, which makes the investigations aimed at providing proper solutions all the more difficult.
The employment of cytotoxic substances or drugs in the treatment of cancer tumors is confronted with several problems. Firstly, most drugs used for this purpose exhibit a nonspecific inherent toxicity leading to adverse side effects; on the other hand, because of this inherent toxicity, the mounts which can be administered to patients are limited and in numerous cases, the activity needed at the site of the tumors, is not sufficient any more.
Various means have already been proposed for overcoming these problems, such as the use of a vector for the cytotoxic substance, for example through the incorporation into liposomes. In such a case however, though the inherent toxicity of the cytotoxic substance is temporarily masked and hence has limited side effects on the patient, its activity is not always restored at the site of the tumor to the desired level of effectiveness.
Furthermore, should the tumor cells subjected to such a treatment develop the phenomenon of multiple drug resistance--whether this property be innate or acquired--the cytotoxic substance loses almost totally its effectiveness.
Several substances are known to-day which display in vitro an inhibitory activity against MDR: they are mostly noncytotoxic substances, generally of a hydrophobic nature, such as for example alkaloids. In vitro, their concomitant use with a cytotoxic drug appears to be satisfactory, the so-called MDR phenomenon being significantly inhibited at the cellular level, so that the drug is able to fulfil its function unhindered.
The situation is however quite different, when one tries to apply such results to a living body. The substances inhibiting MDR, alkaloids or others, also exhibit an inherent toxicity which limits their administration to beneath a level (serum level) at which the activity desired (MDR inhibition) is already lost. Furthermore, although the cytotoxic substance is administered in its free form or as liposomes for example, it has been found that a limiting factor of importance was the concomitant increase in the inherent toxicity of the cytotoxic drug, due to a significant change in its pharmacological distribution throughout the body. In fact, when confronted with such difficulties, those skilled in the art are left with barely any option, when it comes to treating in vivo cancer tumors which exhibit the phenomenon of multiple drug resistance (MDR). Quinine, which was recently proposed as an MDR inhibiting substance, is a perfect illustration of this situation and its use in human therapy is limited accordingly.